DESCRIPTION: The chief aim of this revised competing renewal is to provide experimental data that will advance our knowledge of the heterogeneities that exist within ventricular myocardium and the understanding of their contribution to the normal and abnormal function of the heart. The primary objectives include further characterization of a unique subpopulation of cells in the deep layers of ventricular myocardium that the applicants refer to as M cells as well as further definition of the electrophysiologic and pharmacologic distinctions between epicardial and endocardial tissues and cells. The PI will assess the contribution of electrical heterogeneity to the development of a variety of abnormal heart rhythms such as Torsade de Pointes and idiopathic ventricular fibrillation. The specific aims include projects designed to examine to what extent differences in the electrophysiology and pharmacology of the three cell types contribute to electrocardiographic manifestations, including normal T wave, bifid T waves and long QT intervals. The studies propose to test the hypothesis that genetic defects involving cardiac ion channels amplify the heterogeneity normally present in the heart, thus creating the substrate for the development of life-threatening arrhythmias. The approach is a multilevel one designed to provide and integrate information ranging from membrane electrophysiology to clinical electrocardiography. Electrocardiographic, monophasic action potential and electrogram data will be obtained from arterially-perfused left and right ventricular wedge preparations in which the applicants can simultaneously record a transmural ECG and transmembrane potentials from several sites spanning the ventricular wall. These data will be compared and integrated with those obtained from thin sheets of tissue isolated from various depths of the ventricular wall as well as action potential and voltage/patch clamp data obtained from enzymatically dissociated myocytes. Finally, single channel activity will be recorded from cell membrane patches to provide an understanding of the electrical function of the heart at its most basic level. These studies will advance understanding of the ECG as well as our understanding of the complex factors contributing to the development of cardiac rhythm disturbances. The results will also provide new information relative to mechanisms by which drugs exert their antiarrhythmic actions. The long range goal is to generate information that will contribute to a more definitive and less empiric approach in the medical management of cardiac arrhythmias and sudden cardiac death.